Method and apparatus for treating vulnerable plaque

ABSTRACT

An apparatus and method to treat vulnerable plaque. In one embodiment, the apparatus has an elongated catheter body adapted for insertion in a body lumen, with a drug delivery device attached near a distal portion of the elongated body. The drug delivery device is configured to deliver a biologically active agent to stabilize a vulnerable plaque.

This application is a divisional application of co-pending U.S. patentapplication Ser. No. 10/262,151, filed Sep. 30, 2002.

FIELD OF THE INVENTION

The invention, in one embodiment, relates generally to the treatment ofcoronary disease, and more particularly, in one embodiment, to thestabilization of vulnerable plaque.

BACKGROUND OF THE INVENTION

Coronary heart disease is generally thought to be caused by thenarrowing of coronary arteries by atherosclerosis, the buildup of fattydeposits in the lining of the arteries. The process that may lead toatherosclerosis begins with the accumulation of excess fats andcholesterol in the blood. These substances infiltrate the lining ofarteries, gradually increasing in size to form deposits commonlyreferred to as plaque or atherosclerotic occlusions. Plaques narrow thearterial lumen and impede blood flow. Blood cells may collect around theplaque, eventually creating a blood clot that may block the arterycompletely.

The phenomenon of “vulnerable plaque” has created new challenges inrecent years for the treatment of heart disease. Unlike occlusiveplaques that impede blood flow, vulnerable plaque develops within thearterial walls, but it often does so without the characteristicsubstantial narrowing of the arterial lumen which produces symptoms. Assuch, conventional methods for detecting heart disease, such as anangiogram, may not detect vulnerable plaque growth into the arterialwall. After death, an autopsy can reveal the plaque congested inarterial wall that could not have been seen otherwise with currentlyavailable medical technology.

The intrinsic histological features that may characterize a vulnerableplaque include increased lipid content, increased macrophage, foam celland T lymphocyte content, and reduced collagen and smooth muscle cell(SMC) content. This fibroatheroma type of vulnerable plaque is oftenreferred to as “soft,” having a large lipid pool of lipoproteinssurrounded by a fibrous cap. The fibrous cap contains mostly collagen,whose reduced concentration combined with macrophage derived enzymedegradations can cause the fibrous cap of these lesions to rupture underunpredictable circumstances. When ruptured, the lipid core contents,thought to include tissue factor, contact the arterial bloodstream,causing a blood clot to form that can completely block the arteryresulting in an acute coronary syndrome (ACS) event. This type ofatherosclerosis is coined “vulnerable” because of unpredictable tendencyof the plaque to rupture. It is thought that hemodynamic and cardiacforces, which yield circumferential stress, shear stress, and flexionstress, may cause disruption of a fibroatheroma type of vulnerableplaque. These forces may rise as the result of simple movements, such asgetting out of bed in the morning, in addition to in vivo forces relatedto blood flow and the beating of the heart. It is thought that plaquevulnerability in fibroatheroma types is determined primarily by factorswhich include: (1) size and consistency of the lipid core; (2) thicknessof the fibrous cap covering the lipid core; and (3) inflammation andrepair within the fibrous cap.

FIG. 1A illustrates a partial cross-section of an artery having anarrowed arterial lumen caused by the presence of occlusiveatherosclerosis. Plaque accumulates to impede and reduce blood flowthrough the arterial lumen and thus often causes symptoms (e.g., anginapectoris). The arrows indicate the direction of blood flow through thearterial lumen. FIG. 1B illustrates an occlusive atherosclerosis withinan arterial lumen resulting in significant reduction in lumen patency.This type of atherosclerosis can easily be detected through currentdiagnostic methods such as an angiogram. FIG. 1B also illustrates,downstream from the occlusive atherosclerosis, a fibroatheroma type ofvulnerable plaque. The vulnerable plaque, with a lipid core, developsmostly within the arterial wall with minimal occlusive effects such thatit is not easily detected by current diagnostic methods. This ispartially due to a phenomenon known as “positive remodeling,” whichallows the vessel to respond to the presence of disease. Thefibroatheroma vulnerable plaque has grown into the positively remodeledarterial wall so that vessel occlusion has not been manifested. Afibrous cap surrounds the vulnerable plaque.

FIGS. 2A-2C illustrate a cross-sectional view of the accumulation ofvulnerable plaque in the arterial wall. FIG. 2A illustrates an arterialwall that is not affected by atherosclerosis. The normal arterial wallconsists of an intima layer, a media layer, and an adventitia layer. Theintima is in direct contact with the blood flow within the arteriallumen. The intima consists mainly of a monolayer of endothelial cells.The media consists mostly of smooth muscle cells and extracellularmatrix proteins. The outermost layer of the arterial wall, theadventitia, is primarily collagenous and contains nerves, blood vessels,and lymph vessels. FIG. 2B illustrates the large presence of afibroatheroma type vulnerable plaque surrounded by a fibrous cap withinthe arterial wall. The vulnerable plaque consists mainly of a largelipid core. The fibrous cap layer shields the lumen of the artery fromthe thrombogenic components in the core. FIG. 2C illustrates anocclusive thrombosis event resulting from the rupturing of the fibrouscap. Thrombogenic components in the vulnerable plaque contact luminalblood and cause the thrombotic event.

Autopsy studies and other evidence strongly suggest that the presence ofa current acute coronary syndrome (ACS) event and/or existing thrombusat certain plaque sites may correlate to predicting a future ACS eventin a given patient. The latter indicates the likelihood of a priorthrombotic event (e.g., fibroatheroma rupture) after which the plaquewas able to heal itself, or complete occlusion of the vessel was somehowprevented. Autopsy studies also indicate that it is reasonable to expectthat at least one vulnerable plaque could exist in the majority ofcatheterization laboratory patients being treated for arterial blockagefrom visible, occlusive atherosclerosis. Many of the patients at highestrisk, therefore, for future ACS events may already be receivinginterventional treatment, even though current methods to diagnoseocclusive plaques (i.e., non-vulnerable type plaque) are not effectivefor enabling therapy for vulnerable plaque. Furthermore, treating boththe occlusive plaques and the vulnerable plaque in one procedure mightbe beneficial and desirable compared to separate treatments. This wouldprovide a greater convenience to the patient and for the physician.

SUMMARY OF THE INVENTION

An apparatus and method to treat vulnerable plaque are described. In oneembodiment, the apparatus has a an elongated catheter body adapted forinsertion in a body lumen, with a drug delivery device attached near adistal portion of the elongated body. The drug delivery device isconfigured to deliver a biologically active agent to stabilize avulnerable plaque.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by way of example, and notlimitation, in the figures of the accompanying drawings in which:

FIG. 1A illustrates a partial cross-section of an arterial lumen havingocclusive plaque.

FIG. 1B illustrates a partial cross-section of an arterial lumen havingocclusive plaque and vulnerable plaque.

FIGS. 2A-2C illustrate the vessel morphology and the rupturing of avulnerable plaque.

FIGS. 3A-3B illustrate the stabilization a vulnerable plaque by reducingthe size of the lipid core and strengthening and increasing thethickness of the fibrous cap.

FIG. 4 illustrates one embodiment of using a drug delivery stent totreat a vulnerable plaque downstream from an occlusive plaque.

FIGS. 5A-5C illustrate an alternative embodiment of using a drugdelivery stent to treat a vulnerable plaque downstream from an occlusiveplaque.

FIG. 6 illustrates one embodiment of microparticles released towards avulnerable plaque.

FIG. 7 illustrates one embodiment of a stent graft used to treat avulnerable plaque.

FIGS. 8A-8B illustrate cross-sectional views of a stent graft.

FIGS. 9A-9D illustrate various embodiments of using a needle catheter totreat a vulnerable plaque.

FIGS. 10A-10B illustrate one embodiment of a needle catheter.

FIGS. 11A-11D illustrate various methods for treating vulnerable plaque.

FIG. 12 illustrates one embodiment of inducing therapeutic angiogenesisgrowth near a vulnerable plaque.

FIGS. 13A-13B illustrate cross-sectional views of one embodiment of adrug eluting stent that can be used to strengthen and to increase thethickness of the fibrous cap of the vulnerable plaque in a controlledmanner.

DETAILED DESCRIPTION

In the following description, numerous specific details are set forthsuch as examples of specific, components, processes, etc. in order toprovide a thorough understanding of various embodiment of the presentinvention. It will be apparent, however, to one skilled in the art thatthese specific details need not be employed to practice variousembodiments of the present invention. In other instances, well knowncomponents or methods have not been described in detail in order toavoid unnecessarily obscuring various embodiments of the presentinvention. The term “coupled” as used herein means connected directly toor indirectly connected through one or more intervening components,structures or elements. The terms “drugs,” “bioactive agents,” and“therapeutic agents” are used interchangeably to refer to agents (e.g.,chemical substances) to treat, in one embodiment, coronary artery andrelated diseases including for example, atherosclerotic occlusions andvulnerable plaque.

Apparatuses and their methods of use to treat vulnerable plaque aredescribed. In one embodiment, the vulnerable plaque or the region of theartery containing the vulnerable plaque may be treated alone or incombination with treating occlusive atherosclerosis. The benefit is thatany vulnerable, but not yet occlusive plaques would be treated withouthaving to place a therapeutic implant (e.g., a stent) at the vulnerableplaque region. The only implant placed would be that already being usedto scaffold and treat the existing occlusive plaque. In the followingdescription, the stabilization of vulnerable plaque is described withrespect to treatment within the artery. The coronary artery is just oneregion in the body where vulnerable plaque may form. As such, it can beappreciated that the stabilization of vulnerable plaque may be achievedin any vessel of the body where vulnerable plaque may exist.

FIGS. 3A-3B illustrate a cross-sectional view of the stabilization ofvulnerable plaque. FIG. 3A shows a large vulnerable plaque 310 havinglipid core 315 separated from arterial lumen 330 by thin fibrous cap320. Thin fibrous caps and reduced collagen content or degraded collagenin the fibrous caps increase a plaque's vulnerability to rupture. Asillustrated in FIG. 3B, vulnerable plaque 310 has been stabilized bythickening and/or strengthening fibrous cap 320 that separates lipidcore 315 from arterial lumen 330. This reduces the likelihood of fibrouscap 320 rupturing. Additionally, lipid core 315 redistribution hasoccurred in combination with strengthening fibrous cap 320. Vulnerableplaque 310 may also be treated by inducing collateral artery or vesselgrowth near the vulnerable plaque region such that, in the event offibrous cap rupture or occlusive thrombosis, an alternative blood pathexists to bypass the ruptured region (not shown).

Drug Eluting Stents

In one embodiment, a drug eluting stent may be implanted at the regionof vessel occlusion that may be upstream from a vulnerable plaqueregion. As discussed above, autopsy studies have shown that vulnerableplaque regions commonly exist in the vicinity of occlusive plaques. Amedical device, such as a drug eluting stent, may be used to treat theocclusive atherosclerosis (i.e., non-vulnerable plaque) while releasinga drug or biologically active agent to treat a vulnerable plaque regiondistal or downstream to the occlusive plaque. The drug may be releasedslowly over time, and may include for example, anti-inflammatory oranti-oxidizing agents. Biologically active agents may also be releasedinclude cells, proteins, peptides, and related entities.

The eluting stent may have the vulnerable plaque treating drug or agentdispersed on the surface of the stent, or co-dissolved in a matrixsolution to be dispersed on the stent. Other methods to coat the stentwith a vulnerable plaque treating drug include dip coating, spincoating, spray coating, or other coating methods commonly practiced inthe art.

In one embodiment, therapeutic or biologically active agents may bereleased to induce therapeutic angiogenesis, which refers to theprocesses of causing or inducing angiogenesis and arteriogenesis, eitherdownstream, or away from the vulnerable plaque. Arteriogenesis is theenlargement of pre-existing collateral vessels. Collateral vessels allowblood to flow from a well-perfused region of the vessel into an ischemicregion (from above an occlusion to downstream from the occlusion).Angiogenesis is the promotion or causation of the formation of new bloodvessels downstream from the ischemic region. Having more blood vessels(e.g., capillaries) below the occlusion may provide for less pressuredrop to perfuse areas with severe narrowing caused by a thrombus. In theevent that an occlusive thrombus occurs in a vulnerable plaque, themyocardium perfused by the affected artery is salvaged. Representativetherapeutic or biologically active agents include, but are not limitedto, proteins such as vascular endothelial growth factor (VEGF) in any ofits multiple isoforms, fibroblast growth factors, monocytechemoatractant protein 1 (MCP-1), transforming growth factor alpha(TGF-alpha), transforming growth factor beta (TGF-beta) in any of itsmultiple isoforms, DEL-1, insulin like growth factors (IGF), placentalgrowth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1(PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha(TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocytemacrophage colony-stimulating growth factor (GM-CSF), angiogenin,follistatin, and proliferin, genes encoding these proteins, cellstransfected with these genes, pro-angiogenic peptides such as PR39 andPR11, and pro-angiogenic small molecules such as nicotine.

In another embodiment, therapeutic or biologically active agents totreat the vulnerable plaque may be delivered through the bloodstream orvessel wall. These therapeutic or biologically active agents include,but are not limited to, lipid lowering agents, antioxidants,extracellular matrix synthesis promoters, inhibitors of plaqueinflammation and extracellular degradation, estradiol drug classes andits derivatives.

Prospective studies of high-risk patients in whom complex plaques werefound have indicated that many of the ACS events can happen within sixmonths to one year after a patient has an occlusive atherosclerosislesion treated. In other words, there is a clinical reason to believethat it would be efficacious to try and actively treat lesions in thosepatients for a three to six-month period of time after treatment ofocclusive atherosclerosis to prevent a recurrent ACS event. Examples ofdevices to treat vulnerable plaque regions include drug eluting stents,and drug loaded bioerodable and bioadhesive microparticles.

In one embodiment, the polymer may be coated on a stent using dipcoating, spin coating, spray coating or other coating methods known inthe art. The drug can alternatively be encapsulated in microparticles ornanoparticles and dispersed in a stent coating. A diffusion limitingtop-coat may optionally be applied to the above coatings. The activeagents may optionally be loaded on a stent together either by addingthem together to the solution of the matrix polymer before coating, orby coating different layers, each containing a different agent orcombination of agents. The drug eluting stent can alternatively have anactive agent or a combination of agents dispersed in a bioerodable stentforming polymer.

Vulnerable plaque regions may also be treated independent of treatingocclusive lesions near the vulnerable plaque regions. In anotherembodiment, a vulnerable plaque treatment drug or biologically activeagent may be injected through or around the fibrous cap of a vulnerableplaque. Alternatively, in the event of a thrombotic event, a drug may beinjected to prevent complete occlusion of the vessel. In one embodiment,a needle catheter may be used to inject the drug. The needle cathetermay be modified to accommodate the following targets around thevulnerable plaque: fibrous cap, proteoglycan-rich surface layer,subintimal lipid core, proximal or distal regions of the plaque, mediacontaining smooth muscle cells around the lipid core, andperi-adventitial space. In another embodiment, the needle catheter mayinclude a sensing capability to determine penetration depth of theneedle. Furthermore, the needle catheter may be configured to adoptballoons of various sizes to control the angle of needle penetration.Moreover, the use of balloons would enable accurate penetration of theneedle at the desired target.

In another embodiment, a drug eluting stent may be used to strengthen orincrease the thickness of the fibrous cap of the vulnerable plaque in acontrolled manner. Increasing the thickness of the fibrous cap mayredistribute and lower the stresses in the fibrous cap. This maystabilize the plaque and prevent it from rupturing.

Referring to FIG. 4, a drug delivery stent 450 to treat a vulnerableplaque region is illustrated. Stent 450 is disposed in an arterial lumen430 to treat both occlusive plaque 460 and vulnerable plaque 410 locateddownstream from occlusive plaque 460. As illustrated, stent 450 releasesa drug (indicated by arrows 470) to treat the vulnerable plaque 410. Asdiscussed above, vulnerable plaque regions commonly exist near occlusiveplaque, and treating both might be advantageous over separateprocedures. Occlusive plaque 460 has grown to cause a narrowing of thearterial lumen 430. Stent 450 is shown in a state before expansion toenlarge the diameter of the arterial lumen 430. A dilation balloon (notshown) may be used to expand stent 450, or stent 450 may be made of amaterial that self-expands (e.g., Nitinol) so that a dilation balloon isnot needed.

As illustrated in FIG. 4, vulnerable plaque 410 is located downstream ofthe occlusive plaque 460 but does not show any vessel occlusion.Vulnerable plaque 410 has soft lipid core 415 with fibrous cap 420separating vulnerable plaque 410 from arterial lumen 430. As indicatedby arrows 470, stent 450 releases a drug or biologically active agentthrough the bloodstream of arterial lumen 430 to treat vulnerable plaque410. In one embodiment, lipid lowering agents may be released. Loweringof serum LDL cholesterol may lead to a reduction in the amount ofcholesterol entering vulnerable plaque 410, and increases high densitylipoprotein (HDL) cholesterol which may contribute to active LDL removalfrom the vessel wall 425. Animal studies have shown that removal oflipid increases the relative collagen content of fibrous cap 420 andcould increase the production of collagen, favoring vulnerable plaquestabilization. Lipid lowering animal studies suggest this also treatsvulnerable plaque 410 by reducing local inflammation and the expressionand activity of matrix-degrading enzymes, favoring collagen accumulationin fibrous cap 420, making it more resistant to rupture. Lipid loweringagents may also change the composition of lipid core 415 to promoteplaque stabilization. It is thought that the lipid lowering agents mayconvert the high concentration of cholesterol esters to insolublecholesterol monohydrate crystals, resulting in a more stiff lipid core415 that is more resistant to plaque rupture. Lipid lowering agentsinclude, but are not limited to hydroxy-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, niacin, bile acid resins, and fibrates.

Examples of doses of agents which may be used with embodiments of theinvention, such as a drug delivery stent (i.e., the stent having beenloaded with a drug which is eluted/released over time or a needlecatheter) are described herein. The particular effective dose may bemodified based on therapeutic results, and the following exemplary dosesare acceptable initial levels which may be modified based on therapeuticresults.

In an alternative embodiment, antioxidants may be released from stent450. The oxidation of LDL cholesterol appears to have negative impactupon vessel processes during atherogenesis. Oxidized LDL binds to cellreceptors on macrophages and contributes to foam cell formation. Assuch, antioxidants, through their inhibition of LDL oxidation, maycontribute to plaque stabilization. Antioxidants may also promote plaquestabilization by reducing matrix degradation within vulnerable plaque410. Examples of antioxidants include, but are not limited to vitamin Eα-tocopherol), vitamin C, and β-carotene supplements. Additionally, HMGCoA reductase inhibitors may also reduce oxidized LDL levels byincreasing the total antioxidant capacity of plasma.

Lipid lowering agents such as statins and antioxidants may beadministered at a level of about 0.5 mg/kg per day; higher doses (e.g.,5 times higher) appear to inhibit angiogenesis. See Weis et al., StatinsHave Biphasic Effects on Angiogenesis, Circulation, 105(6):739-745 (Feb.12, 2000). This dosage level may be achieved by loading a stent withabout 10-600 μg of the statin, where the stent is designed to elute thestatin over a period of 8 weeks. In one embodiment, the stent may have alength of 13 mm and a diameter of 3 mm. In one embodiment, the stent mayhave a drug release rate of 150 μg over 10 hours, or 15 μg per hour. Inanother embodiment, the stent may have a lower release rate of about 20μg over 10 hours, over 2 μg per hour. Additionally, a compound called“AGI-1067”, developed by AtheroGenics, Inc. of Alpharetta, Ga., may beloaded onto the stent. AGI-1067 has been shown in studies to have directanti-atherosclerotic effect on coronary blood vessels, consistent withreversing the progression of coronary artery disease.

In an alternative embodiment, extracellular matrix synthesis promotersmay be released from stent 450. Reduced collagen content in fibrous cap420 may result from decreased synthesis of extracellular matrix bysmooth muscle cells (SMC) and/or increased breakdown by matrix-degradingproteases, thereby leading to thinning and weakening of fibrous cap 420,predisposing vulnerable plaque 410 to rupture with hemodynamic ormechanical stresses.

Vascular SMC synthesize both collagenous and noncollagenous portions ofthe extracellular matrix. Lack of sufficient SMC to secrete and organizethe matrix in response to mechanical stress could render fibrous cap 420more vulnerable to weakening by extracellular matrix degradation.Atherosclerosis and arterial injury lead to increased synthesis of manymatrix components. In contrast, vulnerable plaque, in general, lacks asufficient quantity of healthy matrix to provide strength to the fibrouscap to prevent rupture. Thus, promotion of SMC proliferation may lead toplaque stabilization. Delivery of cytokines and growth factors may alsoachieve SMC proliferation. SMC promoters and proliferative agents suchas lysophosphatidic acid may be loaded onto a stent for delivery withina vessel. See Adolfsson et al., Lysophosphatidic Acid StimulatesProliferation of Cultured Smooth Muscle Cells from Human BPH Tissue:Sildenafil and Papaverin Generate Inhibition, Prostate, 51(1):50-8 (Apr.1, 2002). For example, a SMC promoter may be administered at a level ofabout 0.5 mg/kg per day to higher doses of about 2.5 mg/kg per day. Thisdosage level may be achieved by loading a stent with about 10-600 μg ofthe SMC promoter, where the stent is designed to elute the drug over aperiod of 8 weeks. In one embodiment, the stent may have a drug releaserate of 150 μg over 10 hours, or 15 μg per hour. In another embodiment,the stent may have a lower release rate of about 20 μg over 10 hours,over 2 μg per hour.

In an alternative embodiment, inhibitors of plaque inflammation andextracellular matrix degradation may be released from stent 450.Increased matrix degrading activity associated with enzymes derived fromcells such as vascular SMC, macrophages and T lymphocytes is a commonfinding in vulnerable plaque. Studies suggest that matrixmetalloproteinases (MMPs) are involved in matrix degradation. Plaquestabilization could be achieved through inhibition of extracellularmatrix degradation by preventing the accumulation of macrophages and Tlymphocytes in the vulnerable plaque or by inhibiting the proteolyticenzyme cascade directly. Possible methods to achieve MMP inhibitioninclude increasing the levels of natural inhibitors (TIMPS) either byexogenous administration of recombinant TIMPs or administratingsynthetic inhibitors. Synthetic inhibitors of MMPs, includingtretracycline-derived antibiotics, anthracyclines and synthetic peptidesmay also be used. MMP inhibitors may be themselves antioxidants andstatins based on preclinical animal data. Studies have shown MMPinhibitors, such as cerivastatin to significantly reduce tissue levelsof both total and active MMP-9 in a concentration-dependent manner. SeeNagashima et al., A 3-hydroxy-3-methylglutaryl Coenzyme A ReductaseInhibitor, Cerivastatin, Supresses Production of MatrixMetalloproteinase-9 in Human Abdominal Aortic Aneurysm Wall, J. VascularSurgery, 36(1);158-63 (July 2002). As with statins as described above,MMP inhibitors may be administered at a level of about 0.5 mg/kg per dayto higher doses of about 2.5 mg/kg per day. This dosage level may beachieved by loading a stent with about 10-600 μg of the SMC promoter,where the stent is designed to elute the drug over a period of 8 weeks.In one embodiment, the stent may have a drug release rate of 150 μg over10 hours, or 15 μg per hour. In another embodiment, the stent may have alower release rate of about 20 μg over 10 hours, over 2 μg per hour.Additionally, Avasimibe, an ACAT (Acyl-CoA: cholesterol acyltransferase)inhibitor, in the 10 mg/kg range appears to impact MMPs and plaqueburden, as well as monocyte adhesion. See Rodriguez and Usher,Anti-atherogenic Effects of the acyl-CoA: Cholesterol AcyltransferaseInhibitor, Avasimibe (CI-1011), in Cultured Primary Human Macrophages,Atherosclerosis, 161(1); 45-54 (March 2002).

Dosages and concentrations described above are exemplary, and otherdosages may be applied such that when delivered over a biologicallyrelevant time at the appropriate release rate, gives a biologicallyrelevant concentration. The biologically relevant time may depend on thebiologic target but may range from several hours to several weeks withthe most important times being from 1 day to 42 days. Dosages may alsobe determined by conducting preliminary animal studies and generating adose response curve. Maximum concentration in the dose response curvecould be determined by the solubility of a particular compound or agentin the solution and similarly for coating a stent.

In yet another alternative embodiment, the active agent may inducecollateral artery or vessel growth (i.e., angiogenesis orarteriogenesis) near the vulnerable plaque region such that, in theevent of a plaque rupture and subsequent occlusive thrombosis, secondaryblood paths may bypass the ruptured region and allow for continued bloodflow throughout the artery. FIG. 12 illustrates one embodiment ofarterial section 1200 with collateral vessels that have been inducedwith an active agent. Collateral vessels 1250, 1251, 1252 and 1253provide paths for blood flow to continue through arterial section 1200either temporarily until the occlusion is treated, or permanently toprovide greater blood flow. The active agent has been delivered throughdrug delivery stents 1240 and 1242. Primary artery 1230 branches intosections 1231, 1232, and 1233 and arrows 1205 indicate the direction ofblood flow through arterial section 1200. Vulnerable plaque 1210 isdisposed within arterial branch 1232. Stent 1240 induces the growth ofcollateral vessels 1250, 1251 and 1252 around vulnerable plaque 1210.Collateral vessel 1251 starts upstream (near stent 1240) from vulnerableplaque 1210 and ends just downstream from vulnerable plaque 1210.Collateral vessel 1250 starts upstream from vulnerable plaque 1210 andends further downstream of arterial branch 1232. Collateral vessel 1252starts upstream from vulnerable plaque 1210 and ends at arterial branch1233.

Alternatively, collateral vessel growth may be induced from an arterialbranch that does not contain a vulnerable plaque. Stent 1242 carrying anactive agent is disposed within arterial branch 1231 which inducescollateral vessel 1253 from arterial branch 1231 to branch 1233. Assuch, collateral vessel 1253 may provide an alternate pathway forcontinued blood flow in the event vulnerable plaque 1210 ruptures.Although therapeutic or biologically active agents for angiogenesis andarteriogenesis have been described above with respect to drug elutingstents, other types of medical devices may be utilized. In oneembodiment, for example, needle catheters may be used to deliver agentsto induce angiogenesis and/or arteriogenesis. Needle catheters aredescribed in greater detail below with respect to FIGS. 9-10.

In one embodiment, therapeutic or biologically active agents may bereleased to induce arteriogenesis or angiogenesis either downstream, oraway from the vulnerable plaque to the myocardium. In the event that anocclusive thrombus occurs from a vulnerable plaque, the myocardiumperfused by the affected artery may be salvaged. Representativetherapeutic or biologically active agents include, but are not limitedto, proteins such as vascular endothelial growth factor (VEGF) in any ofits multiple isoforms, fibroblast growth factors, monocytechemoatractant protein 1 (MCP-1), transforming growth factor alpha(TGF-alpha), transforming growth factor beta (TGF-beta) in any of itsmultiple isoforms, DEL-1, insulin like growth factors (IGF), placentalgrowth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1(PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha(TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocytemacrophage colony-stimulating growth factor (GM-CSF), angiogenin,follistatin, and proliferin, genes encoding these proteins, cellstransfected with these genes, pro-angiogenic peptides such as PR39 andPR11, and pro-angiogenic small molecules such as nicotine. In oneembodiment, 10-600 μg of one or a mixture of these agents may be loadedonto a stent for delivery within a vessel. These agents may have arelease rate for up to eight weeks. In another embodiment, a stent maybe loaded with 300 micrograms of an angiogenic agent with a release rateof eight weeks. Alternatively, a dose may be determined by those skilledin the art by conducting preliminary animal studies and generating adose response curve. Maximum concentration in the dose response curvewould be determined by the solubility of the compound in the solution.

In using drug eluting stents and related technology to deliver thevulnerable plaque treatment agent (e.g., stent 450 of FIG. 4), theactive agent may be dispersed or co-dissolved directly in a solution ofa matrix such as ethylene vinyl alcohol, ethylene vinyl acetate,poly(hydroxyvalerate), poly (L-lactic acid), poly(D,L-lactic acid),poly(glycolic acid), poly(lactide-co-glycolide) polycaprolactone,polyanhydride, polydiaxanone, polyorthoester, polyamino acids,poly(trimethylene carbobnate), or other suitable synthetic polymers. Thepolymer may be coated on a stent using dip coating, spin coating, spraycoating or other coating methods known in the art.

FIGS. 5A-5C illustrate the placement of drug delivery stent 550 to treatboth occlusive plaque 560 and vulnerable plaque 510 localized downstreamfrom occlusive plaque 560. In this example, vulnerable plaque 510 islocated near a branched region of arterial lumen 530. In one embodiment,stent 550 is a self-expanding stent, and is disposed near distal end 542of catheter 540. Catheter 540 is advanced through arterial lumen 530 andpositioned near occlusive plaque 560. Retractable sheath 545 maintainsstent 550 in a crimped and collapsed position so that stent 550 may befit within arterial lumen 530. As illustrated in FIG. 5A, as sheath 545retracts, stent 550 expands and applies physical pressure to occlusiveplaque 560. In effect, stent 550 widens arterial lumen 530 that has beennarrowed because of occlusive plaque 560. FIG. 5B illustrates stent 550in a fully expanded position, allowing normal blood flow througharterial lumen 530.

Stent 550 may be coated with a drug or biologically active agent thatreleases from the surface of stent 550 when sheath 545 retracts andstent 550 becomes exposed to the blood in arterial lumen 530. The flowof the blood through arterial lumen 530 migrates the agent (as indicatedby the arrows 570) towards vulnerable plaque 510. The agent targetsvulnerable plaque 510. In one embodiment, the agent thickens and/orstrengthens fibrous cap 520. In doing so, the likelihood of fibrous cap520 rupturing is reduced. In another embodiment, the distribution, sizeor consistency of lipid core 515 is altered. A combination of agents maybe utilized both to thicken fibrous cap 520 and alter the size orconsistency of lipid core 515 of vulnerable plaque 510 to strengthenfibrous cap 520. FIG. 5C illustrates the treatment effects of deployingstent 550. Occlusive plaque 560 has been treated physically bycompressing it against the arterial wall. Vulnerable plaque 510 has beentreated through strengthening and/or thickening fibrous cap 520 and thefavorable alteration of the size or distribution of the lipid core 515.

A vulnerable plaque treatment agent may be delivered independent oftreating occlusive atherosclerosis. FIG. 6 illustrates a vulnerableplaque treatment agent delivered in the form of a microcapsule ormicroparticle 670. The use of microparticle 670 allows for delivery of atreatment agent in a controlled manner to ensure treatment over adesired period of time. Some microparticles 670 possess thecharacteristic of being degradable at a designated rate.

Microparticles 670 may also be designed to adhere to vessel wall 635 byblending in or coating microparticles 670 with materials that promoteadhesion to vessel wall 635. Microparticles 670 may be renderedbioadhesive by modifying them with bioadhesive materials such asgelatin, hydroxypropyl methylcellulose, polymethacrylate derivatives,sodium carboxymethycellulose, monomeric cyanoacrylate, polyacrylic acid,chitosan, hyaluronic acid, anhydride oligomers, polyycarbophils,water-insoluble metal oxides and hydroxides, including oxides ofcalcium, iron, copper and zinc. Microparticles 670 may be modified byadsorbing the bioadhesive material on microparticles 670 through ionicinteractions, coating the bioadhesive material on the microparticles bydip or spray coating, conjugating the bioadhesive material to thepolymer constituting microparticle 670, or blending in the bioadhesivematerial into the polymer constituting the microparticles 670, beforethe microparticles 670 are formed.

The particle size of microcapsules 670 may be less than about 10 micronsto prevent possible entrapment in the distal capillary bed.Microparticles 670 may be delivered intra-arterially near the site ofvulnerable plaque 610, and also prophylactically at locations that areproximal and distal to vulnerable plaque 610 (not shown). Upon deliverywith infusion catheter 640, microparticles 670 travel a short distancedistally before adhering to vessel wall 630 near vulnerable plaque 610.The active agent of microparticles 670 is then released over time tothicken and/or strengthen fibrous cap 620, alter the size ordistribution of lipid core 615, or both. Microparticles 670 may bedelivered with infusion catheter 640 or any other delivery device knownin the art. In one embodiment, infusion catheter may be a needlecatheter having one or more injection ports to release microparticles670.

Suitable polymers for the controlled-release microparticles 670 include,but are not limited to, poly (L-lactide), poly (D,L-lactide,poly(glycolide), poly lactide-co-glycolide), polycaprolactone,polyanhydride, polydiaxanone, polyorthoesters, polyamino acids, poly(trimethylene carbonate), and combinations thereof. Several methodsexist for forming microparticles 670, including, but not limited tosolvent evaporation, coacervation, spray drying, and cryogenicprocessing.

In solvent evaporation, the polymer is dissolved in a volatile organicsolvent such as methylene chloride. The treatment agent is then added tothe polymer solution either as an aqueous solution containing anemulsifying agent such as PVA, or as a solid dispersion, and stirred,homogenized or sonicated to create a primary emulsion of treatment agentin the polymer phase. This emulsion is stirred with an aqueous solutionthat contains a polymer in the aqueous phase. This emulsion is stirredin excess water, optionally under vacuum to remove the organic solventand harden the microparticles. The hardened microparticles are collectedby filtration or centrifugation and lyophilized.

The microparticles may also be formed by coacervation. In this method, aprimary emulsion of treatment agent in an aqueous phase is formed as inthe solvent evaporation method. This emulsion is then stirred with anon-solvent for the polymer, such as silicone oil to extract the organicsolvent and form embryonic microparticles of polymer with trappedtreatment agent. The non-solvent is then removed by the addition of avolatile second non-solvent such as a heptane, and the microparticlesharden. The hardened microparticles are collected by filtration orcentrifugation and lyophilized.

In spray drying, the treatment agent, formulated as lyophilized powderis suspended in a polymer phase consisting of polymer dissolved in avolatile organic solvent such as methylene chloride. The suspension thenspray dried to produce polymer microparticles with entrapped treatmentagent.

Microparticles may also be formed by cryogenic processing. In thismethod, the treatment agent, formulated as lyophilized powder issuspended in a polymer phase consisting of polymer dissolved in avolatile organic solvent such as methylene chloride. The suspension issprayed into a container containing frozen ethanol overlaid with liquidnitrogen. The system is then warmed to −70° C. to liquefy the ethanoland extract the organic solvent from the microparticles. The hardenedmicroparticles are collected by filtration or centrifugation andlyophilized.

FIGS. 13A-13B illustrate cross-sectional views of one embodiment of adrug eluting stent that may be used to increase the thickness orstrengthen, in a controlled manner, the fibrous cap near a vulnerableplaque. Strengthening of and increasing the thickness of the fibrous capmay redistribute and lower the stresses in the fibrous cap, effectivelystabilizing the plaque and preventing its rupture.

Cross-sectional views 1300 include lumen 1330 (e.g., an arterial lumen)with lipid core 1315 of a vulnerable plaque and fibrous cap 1320. Stent1340 having stent struts, for example struts 1342, 1344, is placedwithin lumen 1330 near lipid core 1315 and fibrous cap 1320. In oneembodiment of using a drug eluting stent, stent 1340 serves as a vehiclefor delivering an appropriate therapeutic or biologically active agentto the site of the vulnerable plaque. After stent 1340 has been deployedat a desired location, it may cause platelet deposition, fibrosis andneointimal formation in the stented region. This fibromuscular responsemay cause the original fibrous cap 1320 thickness to increase, therebylowering the stresses in fibrous cap 1320 (as illustrated in FIG. 13B).This additional hyperplasia, combined with original fibrous cap 1320produced by stent 1340 can be thought of as a “neo-cap.” Neo-cap 1360,as illustrated in FIG. 13B, has developed near the inner diameter ofstent 1340. The controlled release of a drug or biologically activeagent from stent 1340 may allow an increase in fibrous cap 1320thickness because of the injury sufficient to stabilize lipid core 1315,but may minimize or prevent excessive restenosis. The type ofbiologically active agent, the dosage, release rate and the duration ofrelease may influence the growth of neo-cap 1360. Therefore, bycontrolling these factors the growth of neo-cap 1360 may be controlled.After the thickness of fibrous cap 1320 has been increased and lipidcore 1315 has been stabilized, the size of lumen 1330 may be increasedby balloon angioplasty if necessary.

The biologically active agent used for controlling fibrous cap 1320growth may be delivered using a metal stent platform (e.g., stent 1340).The drug may be released through a polymer membrane-matrix system thatis deposited on the surface of the stent. Polymers such as EVAL can beused for the membrane-matrix system. Several choices of metals areavailable for making the stent, including but not limited to, stainlesssteel, cobalt-chromium alloy and shape-memory alloys such as Nitinol.Depending on the design of the stent and delivery system, it may bepossible to direct the biologically active agent to act in specificlocations of interest in the vulnerable plaque. For example,biologically active agents which are anti-inflammatory in nature may beoptimally delivered into or around the plaque shoulder regions, a siteof inflammatory cell accumulation where the lipid core edges meet thenormal wall opposite the vulnerable plaque. Conversely, it may bepossible to direct the biologically active agent away from specificlocations of interest in the vulnerable plaque. For example,biologically active agents which are anti-restenotic, such asActinomyocin-D, may be directed to act away from the expected regions ofhigh stress in fibrous cap 1320, which cover lipid core 1315 in general.These regions would be the shoulder regions or the portion of fibrouscap 1320 centered circumferentially along lipid core 1315 edge nearestlumen 1330. And finally, it may also be possible to design stent 1340 orother types of delivery systems that selectively diffuse a biologicallyactive agent appropriately, by leveraging through stent 1340 design thestress-assisted diffusion properties at the stent-plaque interface inthese select regions.

The biologically active agent may also be delivered using abiodegradable polymeric stent. In this case, after the biologicallyactive agent has eluted from the stent, the stent degrades within acertain period of time leaving behind a stabilized plaque. The polymersavailable for making the stent include poly-L-lactide,polyglycolic/poly-L-lactic acid (PGLA), Poly-L-latic acid (PLLA),poly-L-lactide, polycaprolactone (PCL),poly-(hydroxybutyrate/hydroxyvalerate) copolymer (PHBV) or shape memorypolymers such as a compound of oligo(e-caprolactone) dimethacrylate andn-butylacrylate.

Examples of therapeutic or biologically active agents include but arenot limited to rapamycin, actinomycin D (ActD) and their derivatives,antiproliferative substances, antineoplatic, antinflammatory,antiplatelet, anticoagulant, antifebrin, antithrombin, antimitotic,antibiotic and antioxidant substances. Examples of antineoplasticsinclude taxol (paclitaxel and docetaxel). Examples of antiplatelets,anticoagulants, antifibrins and antithrombins include sodium heparin,low molecular weight heparin, hirudin, IIb/IIIa platelet membranereceptor antagonist and recombinant hirudin. Examples of antimitoticagents include methotrexate, azathioprine, vincristine, vinblastine,fluororacil, adriamycin and mutamycin. Examples of cytostatic orantiproliferative agents include angiopeptin, calcium channel blockers(such as Nifedipine), Lovastatin (an inhibitor of HMG-CoA reductase, acholestrol lowering drug from Merck). Other therapeutic or biologicallyactive agents which may be utilized include alpha-interferon,genetically engineered epithelial cells and dexamethasone. Dosagescomparable to that described above with respect to drug eluting stentsmay be used.

Stent Grafts

In one embodiment, a stent graft may be used for the treatment ofvulnerable plaque. The stent graft may have a thin, expandablepolytetrafluoroethylene (ePTFE) cylindrical tube affixed to an innersurface of a self-expandable stent. The inner surface of the ePTFE tubemay have a layer of endothelial cells. The endothelial cells, whendispersed near the vulnerable plaque region, may promote cell migrationto form a fully lined monolayer on the lumen surface. The stent graftmay also shield existing vulnerable plaque from the possibility of anacute, thrombotic event. If the plaque ruptures, a cascade ofblood-vessel wall interactions occurs, resulting in thrombosis andultimately partial or total arterial occlusion. Therefore, shieldingvulnerable plaque from the vessel lumen would eliminate the possibilityof plaque contents being exposed to blood flow in case of rupture. Inaddition, the stent graft may provide reinforcement to the fibrous capand reduce any physical stress placed on it due to the size of the lipidcore.

FIG. 7 illustrates another embodiment for treating vulnerable plaque inwhich stent graft 750 is deployed near vulnerable plaque 710. Stentgraft 750 has a thin expandable polytetrafluoroethylene (ePTFE)cylindrical tube 754 affixed to inner surface 751 of self-expandablestent 752. Inner surface 755 of ePTFE tube 754 has a layer ofendothelial cells 756. The layer of endothelial cells 756 promotes cellmigration that eventually forms a complete monolayer on the surface ofarterial lumen 730. As such, stent graft 750 shields existing vulnerableplaque 710 from an occlusive thrombosis event. Moreover, stent graft 750may provide reinforcement to fibrous cap 720 and reduce any increasedphysical stress placed on it in vivo due to lipid core 715 presence orother hemodynamic forces.

ePTFE tube 754 serves as a physical barrier between vulnerable plaque710 and arterial lumen 730. Because ePTFE lumen surface 755 acts as anarterial equivalent, ePTFE tube 754 should remain free from occlusion.In one embodiment, the ePTFE tube 754 is made anti-thrombotic by surfacetreatment. The surface of ePTFE tube 754 may be made anti-thrombotic foruse as a vascular graft by seeding surface 755 with endothelial cells756. Endothelial cells 756 seeded within vascular grafts have been shownto promote cell migration that eventually form a fully lined monolayeron a lumen surface.

Several approaches exist to seed stent graft 750 with endothelial cells756. In one embodiment, a pressurized sodding technique may be used inwhich ePTFE tube 754 is expanded to 5 psi using media that containendothelial cells. Endothelial cells 756 are isolated from the caninefalciform ligament fat. Endothelial cells may also be isolated fromhuman liposuction fat micro-vessel, umbilical veins, and othercomparable sources.

Stent graft 750 may be disposed near a target vulnerable plaque 710 in amanner similar to that of a drug eluting stent 450, 550 at an occlusivesite discussed above (e.g., with respect to FIGS. 4 and 5A-5C). Stentgraft 750 is disposed near a distal end of a catheter (not shown). Thecatheter is passed through arterial lumen 730 so that stent graft 750 ispositioned near vulnerable plaque 710. A retractable sheath (not shown)maintains the stent graft in a crimped position so that the stent graftmay be advanced within arterial lumen 730. As illustrated in FIG. 7,stent graft 750 expands and applies physical pressure to fibrous cap 720surrounding vulnerable plaque 710. FIG. 7 illustrates stent graft 750 ina fully expanded position, allowing normal blood flow through arteriallumen 730.

FIGS. 8A-8B illustrate cross-sectional views of stent graft 850 havinginner tube 854 lined with endothelial cells 856 for treating vulnerableplaque. A self-expandable stent 852 is used as structural support tokeep stent graft 850 secured in place within arterial lumen 730. Aself-expandable stent may be advantageous over a balloon expandablestent. A self-expandable stent does not require an internal lumenpressure to expand, and so any seeded cells 856 are kept intact. Incontrast, a balloon expandable stent could damage cells 856 of stentgraft 850 when expanded. The self-expanding stent 852 may be made from ashape memory alloy such as NiTi (e.g., Nitinol). In order to provideadditional flexibility to stent 852, stent links (e.g., 860, 861) may beeliminated from stent 852. In an alternative embodiment, stent 852 mayhave a series of shape memory metallic rings (not shown) bonded to theouter surface of ePTFE tubing 854.

Various techniques are available to bond ePTFE tube 854 to stent 852.For example, to bond the ePTFE tube to the metal, a primer is firstapplied to the metallic portions (e.g., 860, 861) of stent 852. Theserings are then inserted over ePTFE tube 854. Silicon adhesive is used tobond metallic rings 860, 861 to ePTFE tubing 854. The stent graft iscured at about 150° C. for approximately 15 minutes. The siliconadhesive seeps through the ePTFE tube matrix and after curing acts as amedium that mechanically fastens the ePTFE tube to the metal. The innersurface of the polymeric tube is then seeded with endothelial cells.

In addition to the shape memory alloys, stent rings 860, 861 may also bemade from shape memory polymers. Various shape memory polymers withgreat potential for biomedical applications are currently in theresearch phase. For example oligo(e-caprolactone) dimethacrylate andn-butyl acrylate are two monomeric compounds that, when combined,generate a family of polymers that exhibit excellent shape memorycharacteristics. The oligo(e-caprolactone) dimethacrylate furnishes thecrystallizable “switching” segment (characteristic of shape memorymaterials) that determines both the temporary and permanent shape of thepolymer. By varying the amount of the comonomer, n-butyl acrylate, inthe polymer network, the cross-link density can be adjusted. This allowsthe mechanical strength and transition temperature of the polymers to betailored over a wide range. Therefore, the stent incorporating thesepolymers can be deployed using their shape memory characteristics.Furthermore, other polymers such as polyurethane and ultra highmolecular weight polyethylene (UHMWPE) can also be used for tubing usedin the stent graft.

In an alternative embodiment, stent graft 850 may also be used as anapparatus for local drug delivery. Stent graft 850 may be loaded withanti-restenotic, anti-thrombotic, or other vulnerable plaque treatmentagents (e.g., as discussed above with respect to FIGS. 4 and 5A-5C).Furthermore, in yet another alternative embodiment, stent graft 850 maybe radioactively enhanced or incorporated with a material that generatesa magnetic susceptibility artifact of stent graft 850.

Needle Catheter

In another embodiment, a vulnerable plaque treatment drug orbiologically active agent may be injected through or around a vulnerableplaque region. In one embodiment, a needle catheter may be used toinject the biologically active agent. The needle catheter may beadjusted to penetrate various targets around the vulnerable plaqueincluding, but not limited to: fibrous cap, proteoglycan-rich surfacelayer, subintimal lipid core, proximal or distal regions of thevulnerable plaque, media containing smooth muscle cells around the lipidcore, and the periadventitial space.

In an alternative embodiment, the needle catheter may include sensingcapabilities to determine the depth of penetration of the needle, aswell as dial-in needle extension. Furthermore, different angle balloonsmay be added in order to use case-specific ramp angle to penetrate intothe vulnerable plaque region while positioning the needle catheter belowthe actual occlusion. The needle catheter may be placed proximal ordistal to the vulnerable plaque region because studies have shown celllocalization, activity, and apoptosis have preferential occurrence inthe upstream or downstream parts of vulnerable plaque regions.

FIG. 9A illustrates a cross-sectional view of one embodiment of needlecatheter 950 that may be used to inject a vulnerable plaque treatmentagent into arterial wall 980 near vulnerable plaque 910. Vulnerableplaque 910 has developed within arterial wall 980, separated fromarterial lumen 930 by fibrous cap 920. Distal end 941 of catheter 940has inflatable balloon 948 with at least one needle lumen 945 extendingfrom distal end 941 of catheter 940 along proximal end 947 of balloon948. Retractable needle 945 extends from needle lumen 942 and penetratesarterial wall 980. Inflated balloon 948 secures needle catheter 950 at atarget location. Moreover, because needle sheath 942 is coupled alongproximal end 947 of balloon 948, inflated balloon 948 provides apenetration angle for needle 945. Needle catheter 950, as illustrated,has two needles 945, 946 extending from distal end 941 of catheter 950.Any number of needles may be utilized with needle catheter 950. Forexample, in an alternative embodiment, the needle catheter may have onlyone needle for injecting a vulnerable plaque treatment agent.

As illustrated, needle catheter 950 targets lipid core 915 of vulnerableplaque 910 directly. In one embodiment, a lipid lowering agent may beinjected into vulnerable plaque 910, or agents which could change lipidcore properties could be injected. PEG with an aldehyde/gluteraldehydemix may be injected into lipid core 915 potentially cross-linkingvulnerable plaque 910 components to inhibit erosion, rupture, or otherforms of destabilization. Other vulnerable plaque treatment agents maybe used, including antioxidants, and extracellular matrix synthesispromoters (e.g., as discussed with respect to FIGS. 4 and 5A-5C).

Needle catheter 950 may also be configured to include a feedback sensor(not shown) for mapping the penetration depth of needles 945, 946. Theuse of a feedback sensor provides the advantage of accurately targetingthe injection location. Depending on the type of treatment agent usedand treatment desired, the target location for delivering the treatmentagent may vary. For example, it may be desirable to inject a drug nearfibrous cap 920 or media 984 of arterial wall 980. Alternatively, it maybe desirable to inject a drug into lipid core 915, or adventitia 986.

In use, distal end 941 of needle catheter 950 is inserted into the lumenof a patient and guided to a vulnerable plaque region. As illustrated inFIG. 9A, distal end 941 of needle catheter 950 is positioned near aproximal end 912 of vulnerable plaque 910. Alternatively, needlecatheter 950 may be positioned near a distal end 914 of vulnerableplaque 910. Vulnerable plaque 910 may be detected using the sensor (notshown) disposed on needle catheter 950. By utilizing a sensor, theinjection site for treating vulnerable plaque 910 may be preciselyidentified.

FIGS. 10A and 10B illustrate cross sectional views of one embodiment ofa needle catheter for injecting a vulnerable plaque treatment drug orbiological agent. FIG. 10 illustrates needle catheter 1001 with sensingcapabilities having elongated catheter body 1010 that surrounds needlelumen 1012 and inner lumen 1014. Housed within inner lumen 1014 arefluid lumen 1016 and inner member 1018 that also contains guide wire1020, guide wire lumen 1022, and ultrasonic element lumen 1024.Inflatable balloon 1026 is coupled to inner lumen 1014 and the innermember 1018. Proximal end 1028 of balloon 1026 is coupled to distal end1030 of inner lumen 1014 and distal end 1032 of balloon 1026 is coupledto distal end 1036 of inner member 1018.

In an alternative embodiment, both guide wire 1022 and retractableultrasonic element 1034 may be housed within inner member 1014. Elongatebody 1010 surrounds inner member 1014 and needle lumen 1012. Housedwithin inner lumen 1014 are inner member 1018 and fluid lumen 1016.Inner member 1018 surrounds guide wire 1022 and retractable ultrasonicelement 1034. Inflatable balloon 1026 is coupled to inner lumen 1014 andinner member 1018. Proximal end 1028 of balloon 1026 is coupled todistal end 1030 of inner lumen 1014 and distal end 1032 of balloon 1026is coupled to distal end 1036 of inner member 1018.

The ultrasonic element lumen 1024 of inner member 1018 housesretractable ultrasonic element 1034. The distal end of the ultrasonicelement has an ultrasound transducer or transducer array and theproximal end contains the associated co-axial cable that connects to animaging display system (not shown). Ultrasonic waves generated by theultrasonic element impinge on the surface of a vulnerable plaque orvulnerable plaque region. The timing/intensity of the ultrasonic wavesreflected back to the transducer differentiates between the variousanatomic boundaries or structures of the vulnerable plaque region, forexample, the various layers of an arterial wall. The waves detected bythe transducer are converted to electric signals that travel along thecoaxial cable to the imaging system. The electrical signals areprocessed and eventually arranged as vectors based on the digitizeddata. In one embodiment, the ultrasound transducer has piezoelectriccrystal configured for optimal acoustic output efficiency and energyconversion. In alternative embodiments, the crystal is made of PZT orlead-ceramic materials such as PbTiO₃ (lead titanate) or PbZrO₃ (leadzirconate).

As further illustrated in FIGS. 10A-10B, retractable needle 1013 ishoused in needle lumen 1012 and freely movable therein. The hollow,tubular shaped needle 1013, having an inner diameter within a range ofapproximately 0.002 inch to 0.010 inch (5.1×10⁻³ cm to 25.4×10⁻³ cm) andan outer diameter within the range of approximately 0.004 inch to 0.012inch (10.2×10⁻³ cm to 30.5×10⁻³ cm), provides a fluid channel thatextends from proximal end 1040 to distal end 1042 of needle 1013. Distalend 1042 of needle 1013 has a curved tip. In one embodiment, needle 1013has an angle of curvature of about 30 degrees to 90 degrees. Thecurvature of needle 1013 facilitates placement of the needle tip near orwithin a desired target of a vulnerable plaque region. Needle 1013 maybe formed from a variety of metals including, but not limited tostainless steel, NiTi (nickel titanium) (e.g., Nitinol) or othercomparable semi-rigid materials.

Proximal end 1040 of needle 1013 is coupled to adapter 1050 that couplesneedle 1013 to needle lock 1052 and needle adjustment knob 1054. Needlelock 1052 is used to secure needle 1013 in place and prevent furthermovement of needle 1013 within an arterial lumen once needle 1013 isplaced in the target position. Needle adjustment knob 1054 controlsaccurate needle extension out of the distal end of the catheter anddepth of penetration into the vulnerable plaque region. As such,movement of needle adjustment knob 1054 moves needle 1013 in and out ofneedle lumen 1012. Once needle 1013 has penetrated a target to a desireddepth, needle lock 1052 enables needle 1013 to be secured in placethereby preventing any movement of needle 1013 within needle lumen 1012.

A drug injection port 1060 is disposed near proximal end 1062 of needlecatheter 1001. Drug injection port 1060 couples needle catheter 1001with various dispensing devices such as a syringe or fluid pump. Fluidsinjected into drug injection port 1060 travel through needle 1013 andare dispensed from the distal tip of needle 1013.

FIGS. 9B-9D illustrate embodiments of needle catheter 950 targetingvarious regions near a vulnerable plaque for injection of a vulnerableplaque treatment agent. As discussed above, needle catheter 950 may havea feedback sensor (e.g., ultrasonic element 1034 of FIG. 10B) todetermine and control a penetration depth for needles 945, 946. Thesensor provides the advantage of accurately targeting a desiredinjection site. As such, needle catheter 950 may inject a vulnerableplaque stabilizing drug or biologically active agent into fibrous cap920 as illustrated in FIG. 9B, regions within the subintimal space 982of arterial wall 980 as illustrated in FIG. 9C, or regions distal tovulnerable plaque 910 as illustrated in FIG. 9D.

For example, with respect to FIG. 9B antioxidants such as reactiveoxygen scavengers (ROS), vitamin C and E may be injected into fibrouscap 920. The oxidant acts as a matrix-ase inhibitor to preventsignificant collagen degradation within fibrous cap 920.

In another embodiment, needle catheter 950 may also be used as part of abiological or gene therapy method to treat vulnerable plaque 910. Forexample, upregulators of tissue inhibitors of metalloproteinases (TIMPS)may be injected into adventitia 986. TIMPS are expressed by surroundingsmooth muscle cells to downregulate MMP production. Alternatively,recombinant TF pathway inhibitors (TFPI) may one day be injected intolipid core 915 to inhibit thrombosis due to erosion, rupture or otherforms of plaque destabilization.

In yet another embodiment, needle catheter 950 may be used to deliver anagent to induce angiogenesis and/or arteriogenesis as described abovewith respect to FIG. 12. The therapeutic angiogenesis agents and drugsdiscussed above may be injected near a treatment site as an alternativeto delivery by a drug eluting stent.

FIGS. 11A-11D illustrate flowcharts describing methods for stabilizingvulnerable plaque. The methods described with respect to FIGS. 11A-11Dinclude detecting vulnerable plaque. Various techniques may be utilizedto detect the presence and location of vulnerable plaque. For example,an ultrasound probe (IVUS) or an optical coherence tomography probe(OCT) may be guided through the arteries to scan for vulnerable plaque.Alternatively, magnetic resonance imaging (MRI) devices may be able todetect vulnerable plaque. Near Infrared spectroscopy is anothertechnique for detecting vulnerable plaque. For example, certainwavelengths of light penetrate the arterial wall and produce a specificchemical signature that could correlate to vulnerable plaquecomposition. Additionally, thermography may also be used to detectvulnerable plaque. Plaques that rupture tend to be inflamed, and dataindicates this correlates to a higher temperature compared tonon-vulnerable type plaques that do not rupture. As such, a temperaturesensitive probe that measures the temperature of arteries could indicatethe presence of vulnerable plaque. Alternatively, liquid crystalthermography methods may also be used. For example, a balloon materialmade of a thermochromic liquid crystal material may be able to opticallydetect property changes when exposed to increases in temperature. Whenthe balloon contacts a vulnerable plaque, the higher temperature of thevulnerable plaque may be detected by analyzing a beam of light directedtowards the suspected vulnerable plaque region and the balloon materialin contact therewith. The light may undergo a color change in theballoon material as a result of the higher temperature.

FIG. 11A describes a method to treat vulnerable plaque downstream froman occlusive plaque. The occlusive plaque may be treated with a stent orballoon catheter. The vulnerable plaque may be treated by altering thelipid core and/or strengthening or thickening the fibrous capsurrounding the vulnerable plaque. The vulnerable plaque is firstdetected by any one of the techniques described above, including but notlimited to IVUS, OCT, MRI, near infrared spectroscopy, thermography, andliquid crystal thermography. The vulnerable plaque may be downstreamfrom an occlusive plaque that has been detected, for example, with anangiogram. A drug delivery catheter is provided having a vulnerableplaque stabilizing agent. In one embodiment, the drug delivery cathetermay deploy a drug eluting stent. The drug eluting stent is positioned atthe occlusive plaque to widen the arterial lumen whose blood flow hasbeen impeded by the plaque. The vulnerable plaque stabilizing agent isreleased towards a vulnerable plaque region located downstream from therelease site. Alternatively, the agents may be in the form ofmicroparticles to control the release of the agents over time. Theagents released from the drug delivery catheter may include lipidlowering agents, antioxidants, extracellular matrix synthesis promoters,or inhibitors of plaque inflammation and extracellular degradation.

FIG. 1B describes a method to treat vulnerable plaque by inducingcollateral artery or vessel growth to the myocardium downstream from oradjacent to an occlusive plaque. The occlusive plaque may be treatedwith a stent or balloon catheter. By inducing therapeutic angiogenesis(e.g., collateral artery or vessel growth), blood flow is maintained incase a vulnerable plaque ruptures leading to an occlusive thrombosis.The vulnerable plaque is first detected by any one of the techniquesdescribed above, including but not limited to IVUS, OCT, MRI, nearinfrared spectroscopy, thermography, and liquid crystal thermography.The vulnerable plaque may be downstream from an occlusive plaque thathas been detected, for example, with an angiogram.

A drug delivery catheter or stent is provided having an agent thatinduces collateral artery or vessel growth. In one embodiment, the drugdelivery catheter may deploy a drug eluting stent. The drug elutingstent is positioned at the occlusive plaque to widen the arterial lumenwhose blood flow has been impeded by the plaque. The agent to inducecollateral artery or vessel growth is released towards a vulnerableplaque region located downstream from the drug release site.Representative therapeutic or biologically active agents include, butare not limited to, proteins such as vascular endothelial growth factor(VEGF) in any of its multiple isoforms, fibroblast growth factors,monocyte chemoatractant protein 1 (MCP-1), transforming growth factoralpha (TGF-alpha), transforming growth factor beta (TGF-beta) in any ofits multiple isoforms, DEL-1, insulin like growth factors (IGF),placental growth factor (PLGF), hepatocyte growth factor (HGF),prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosisfactor alpha (TBF-alpha), granulocyte stimulating growth factor (G-CSF),granulocyte macrophage colony-stimulating growth factor (GM-CSF),angiogenin, follistatin, and proliferin, genes encoding these proteins,cells transfected with these genes, pro-angiogenic peptides such as PR39and PR11, and pro-angiogenic small molecules such as nicotine.

FIG. 11C describes a method to treat vulnerable plaque by implanting astent graft on the arterial wall near a vulnerable plaque. This methodof vulnerable plaque stabilization may be performed independent oftreating an occlusive plaque. The vulnerable plaque is first detected byany one of the techniques described above, including but not limited toIVUS, OCT, MRI, near infrared spectroscopy, thermography, and liquidcrystal thermography. The stent graft is disposed near a distal end of acatheter and advanced within the arterial lumen and positioned near avulnerable plaque. Retracting a sheath covering the stent graft deploysthe stent graft. In one embodiment, the stent graft has a thin ePTFEcylindrical tube affixed to the inner surface of a self-expandablestent. The inner surface of the stent has a layer of endothelial cells.The layer of endothelial cells promote cell migration that forms a fullylined monolayer on the arterial lumen surface. As such, the stent graftshields existing vulnerable plaque from an occlusive thrombotic event.Moreover, the stent graft provides reinforcement to the fibrous cap andreduces any physical stress placed on it due to the presence of thelipid core and hemodynamic forces.

FIG. 11D describes another method to treat vulnerable plaque. Thevulnerable plaque may be treated by injecting a stabilizing drug orbiologically active agent at various locations within and around thevulnerable plaque. The vulnerable plaque is first detected by any one ofthe techniques described above, including but not limited to IVUS, OCT,MRI, near infrared spectroscopy, thermography, and liquid crystalthermography. A needle catheter is advanced through an arterial lumenand positioned near a proximal end of the vulnerable plaque.Alternatively, the needle catheter may be positioned at or near a distalend of the vulnerable plaque. A sensor disposed on the needle catheterdetermines a penetration depth for the needle catheter. The needlecatheter may be adjusted to penetrate various targets around thevulnerable plaque including, but not limited to: fibrous cap,proteoglycan-rich surface layer, subintimal lipid core, proximal ordistal regions of the vulnerable plaque, media containing smooth musclecells above the lipid core and the adventitial space. The agentsreleased from the drug delivery catheter may include lipid loweringagents, antioxidants, extracellular matrix synthesis promoters,inhibitors of plaque inflammation and extracellular degradation.

In the foregoing specification, the invention has been described withreference to specific exemplary embodiments thereof. It will, however,be evident that various modifications and changes may be made theretowithout departing from the broader spirit and scope of the invention asset forth in the appended claims. The specification and drawings are,accordingly, to be regarded in an illustrative rather than a restrictivesense.

1. An apparatus, comprising: an elongated catheter body adapted forinsertion in a body lumen; and a drug delivery device coupled near adistal portion of said elongated body, said drug delivery deviceconfigured to deliver a biologically active agent to stabilize avulnerable plaque.
 2. The apparatus of claim 1, wherein said drugdelivery device comprises: a balloon disposed at a distal end of saiddrug delivery device; and at least one needle housed within said drugdelivery device, wherein said at least one needle is moveable from aretracted position to an extended position, and wherein an angle ofneedle penetration relative to said elongated catheter body correspondsto an inflation of said balloon.
 3. The apparatus of claim 2, furthercomprising a sensor near said distal portion of said catheter, whereinsaid sensor determines a penetration depth of said at least one needle.4. The apparatus of claim 1, wherein said biologically active agentcomprises lipid lowering agents.
 5. The apparatus of claim 1, whereinsaid biologically active agent comprises antioxidants.
 6. The apparatusof claim 1, wherein said biologically active agent comprisesanti-inflammatory agents.
 7. The apparatus of claim 1, wherein saidbiologically active agent comprises extracellular matrix synthesispromoters.
 8. The apparatus of claim 1, wherein said drug deliverydevice delivers up to 600 μg of said biologically active agent.
 9. Amethod for stabilizing a vulnerable plaque in a lumen wall, comprising:detecting said vulnerable plaque; advancing a needle catheter near saidvulnerable plaque; and delivering a vulnerable plaque stabilizing agentwith said needle catheter near said vulnerable plaque.
 10. The method ofclaim 9, further comprising determining a penetration depth of saidneedle catheter.
 11. (canceled)
 12. The method of claim 9, whereindelivering said vulnerable plaque stabilizing drug comprises targetingan intimal layer near said vulnerable plaque.
 13. The method of claim 9,wherein delivering said vulnerable plaque stabilizing drug comprisestargeting an adventitial layer near said vulnerable plaque.
 14. Themethod of claim 9, wherein delivering said vulnerable plaque stabilizingdrug comprises targeting a media layer near said vulnerable plaque. 15.The method of claim 9, wherein delivering said vulnerable plaquestabilizing drug comprises targeting said lipid core of said vulnerableplaque region.
 16. The method of claim 15, wherein targeting said lipidcore comprises delivering a cross-linking agent.
 17. A method of claim15, wherein targeting said lipid core comprises delivering a matrix-aseinhibitor.
 18. The method of claim 13, wherein targeting saidadventitial layer comprises delivering a collagen synthesis promoter.19. The method of claim 13, wherein targeting said adventitial layercomprises gene therapy.
 20. The method of claim 13, wherein targetingsaid adventitial layer comprises inserting said needle into said bodylumen wall at a point proximal to said vulnerable plaque region, andextending said needle to said adventitial layer.
 21. The method of claim14, wherein targeting said media layer comprises inserting said needleinto said body lumen wall at a point proximal to said vulnerable plaqueregion, and extending said needle to said media layer.
 22. (canceled)23. The method of claim 15, wherein targeting said lipid core comprisesinserting said needle into said body lumen wall at a point proximal tosaid lipid core, and extending said needle to said lipid core.
 24. Themethod of claim 9, wherein said vulnerable plaque stabilizing agentstrengthens said fibrous cap.
 25. The method of claim 9, wherein saidvulnerable plaque stabilizing agent reduces a size of a lipid core ofsaid vulnerable plaque.
 26. The method of claim 9, wherein saidvulnerable plaque stabilizing agent thickens said fibrous cap.
 27. Amethod for treating a vulnerable plaque, comprising: advancing a medicaldevice within a body lumen; and delivering a biologically active agentfrom said medical device, wherein said biologically active agent inducesa therapeutic angiogensesis growth away from said vulnerable plaque tomaintain a blood perfusion in the event of an occlusive thrombosis froma rupturing of said vulnerable plaque.
 28. The method of claim 27,wherein delivering comprises releasing said biologically active agentupstream from said vulnerable plaque.
 29. A method of claim 28, furthercomprising providing a drug delivery catheter to release saidbiologically active agent.
 30. The method claim 27, wherein deliveringcomprises releasing said biologically active agent through a bloodstreamnear said vulnerable plaque.
 31. The method claim 27, wherein deliveringcomprises releasing said biologically active agent towards a lumen wallnear said vulnerable plaque.
 32. The method claim 27, wherein deliveringcomprises sustained-releasing said biologically active agent.
 33. Themethod of claim 32, wherein sustained-releasing said biologically activeagent comprises releasing said biologically active agent over a periodup to about 6 months.
 34. The method of claim 29, wherein said drugdelivery catheter comprises dip coating a drug eluting stent with saidbiologically active agent.
 35. The method of claim 29, wherein said drugdelivery catheter comprises spin coating a drug eluting stent with saidbiologically active agent.
 36. The method of claim 31, wherein releasingsaid biologically active agent towards said lumen wall comprisesadhering a plurality of micro-particles to said lumen wall.
 37. Themethod of claim 27, wherein said biologically active agent is selectedfrom a group consisting of vascular endothelial growth factor (VEGF),fibroblast growth factors, monocyte chemoatractant protein 1 (MCP-1),transforming growth factor alpha (TGF-alpha), transforming growth factorbeta (TGF-beta, DEL-1, insulin like growth factors (IGF), placentalgrowth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1(PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha(TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocytemacrophage colony-stimulating growth factor (GM-CSF), angiogenin,follistatin, proliferin, pro-angiogenic peptides, and pro-angiogenicsmall molecules.
 38. The method of claim 27, wherein delivering saidbiologically active agent induces a therapeutic angiogenesis growth to amyocardium.
 39. The method of claim 27, wherein delivering saidbiologically active agent comprises delivering up to 600 μg of saidbiologically active agent.
 40. An apparatus for stabilizing a vulnerableplaque in a lumen wall, comprising: means for detecting said vulnerableplaque; means for advancing a needle catheter near said vulnerableplaque; and means for delivering a vulnerable plaque stabilizing agentwith said needle catheter near said vulnerable plaque, wherein saidvulnerable plaque stabilizing agent increases a thickness of a fibrouscap.
 41. An apparatus for treating a vulnerable plaque, comprising:means for advancing a medical device within a body lumen; and means fordelivering a biologically active agent from said medical device, whereinsaid biologically active agent induces a therapeutic angiogenesis growthaway from said vulnerable plaque to maintain a blood perfusion in theevent of an occlusive thrombosis from a rupturing of said vulnerableplaque.